Eplerenone, (7α,11α,17α)-9,11-epoxy-17-hydroxy-3-oxo-pregn-4-ene-7,21-dicarboxylic acid, γ-lactone, 7-methyl ester, is a mineralocorticoid receptor antagonist useful in the treatment of high blood pressure and congestive heart failure. It is marketed under the name of INSPRA™.

Most of the patents and literature information dealing with the preparation of Eplerenone are based on the use of the known trienone I as a starting material. In turn, the trienone I is obtained from the natural product Canrenone by 11-bio-hydroxylation followed by mesylation and elimination. The trienone I is then treated with diethylaluminum cyanide to form the 7-cyano derivative II that, after a reduction/oxidation sequence, yields intermediate III.

Crude intermediate III is reacted with diazomethane to provide the methyl ester intermediate IV which is then epoxidized using hydrogen peroxide in the presence of an initiator to yield Eplerenone.

The original patent, U.S. Pat. No. 4,559,332, for the preparation of Eplerenone describes the epoxidation reaction of IV using hydrogen peroxide in the presence of trichloroacetonitrile as initiator. This patent does not disclose any information with respect to the purity of the material obtained, its purification, or the removal of impurities.
When the present inventors repeated the preparation taught in U.S. Pat. No. 4,559,332, it was observed that the purity of the resulting Eplerenone was low (70%) and attempts to purify the resulting product to a level meeting the requisite specifications for use as a pharmaceutical active were unsuccessful [typically, known impurities cannot be >0.2% (w/w)]. In particular, dihydroxylated compounds V and VI, which were isolated and identified, were very difficult to remove. Noteworthy is that similar compounds were mentioned elsewhere in the literature (U.S. Pat. No. 6,887,991), although methods for their removal were not disclosed.

Other patent literature on processes for the synthesis of Eplerenone, for instance WO2001/042272, discloses examples for the purification of Eplerenone by recrystallization; however, the main objective of these patents was the preparation of various polymorphic and solvated forms. Again, even after numerous attempts to remove the dihydroxylated impurities V and VI from crude Eplerenone by recrystallization using these solvents and solvent mixtures, we were unable to obtain satisfactory purities of finished pharmaceutical active.
Therefore, an industrially acceptable method to prepare and purify Eplerenone was required.